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In this investigation a series of polygodial analogues were prepared and investigated for TRPV1\u2010agonist and anticancer activities. These experiments led to the identification of 9\u2010epipolygodial, which has antiproliferative potency significantly exceeding that of polygodial. 9\u2010Epipolygodial was found to maintain potency against apoptosis\u2010resistant cancer cells as well as those displaying the multidrug\u2010resistant (MDR) phenotype. In addition, the chemical feasibility for the previously proposed mechanism of action of polygodial, involving the formation of a Paal\u2013Knorr pyrrole with a lysine residue on the target protein, was demonstrated by the synthesis of a stable polygodial pyrrole derivative. These studies reveal rich chemical and biological properties associated with polygodial and its direct derivatives. These compounds should inspire further work in this area aimed at the development of new pharmacological agents, or the exploration of novel mechanisms of covalent modification of biological molecules with natural products.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.201500360","type":"journal-article","created":{"date-parts":[[2015,10,5]],"date-time":"2015-10-05T05:57:34Z","timestamp":1444024654000},"page":"2014-2026","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Synthetic and Biological Studies of Sesquiterpene Polygodial: Activity of 9\u2010Epipolygodial against Drug\u2010Resistant Cancer Cells"],"prefix":"10.1002","volume":"10","author":[{"given":"Ramesh","family":"Dasari","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas State University  San Marcos TX 78666 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annelise","family":"De\u2005Carvalho","sequence":"additional","affiliation":[{"name":"Laboratoire de Canc\u00e9rologie et de Toxicologie Exp\u00e9rimentale Facult\u00e9 de Pharmacie Universit\u00e9 Libre de Bruxelles  1050 Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek C.","family":"Medellin","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas State University  San Marcos TX 78666 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey N.","family":"Middleton","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry Texas State University  San Marcos TX 78666 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric","family":"Hague","sequence":"additional","affiliation":[{"name":"Laboratoire de Physiologie Cellulaire et Mol\u00e9culaire Facult\u00e9 des Sciences Universit\u00e9 de Picardie Jules Verne  80000 Amiens France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie N. 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